Immune Regulation to Intestinal Bacterial Antigens

描述（由申请人提供）：调节性T细胞是一种CD4+ T细胞亚群，具有免疫抑制活性，已在人类和小鼠中发现。这些细胞通过显性机制发挥耐受性，在干预自身炎症性疾病和移植方面具有明显的治疗意义。我们已经在正常小鼠肠道中鉴定出IL-10产生CD4+ T细胞，这些细胞对肠道细菌抗原有反应，并且在体外和体内具有Treg功能。我们推测这个群体是从成熟的、幼稚的CD4 T细胞前体发育而来的，这些细胞可以识别肠道细菌抗原，而IL-10可以作为识别和研究这些细胞的有用标记物。在本课题中，我们将利用一种基于DO11.10 TCR转基因小鼠的新型抗原特异性结肠炎模型来研究肠道Tregs的起源、功能和维持。我们还将采用一种新的IL-10报告基因敲入小鼠来提供一种功能标记，可用于鉴定、分离和表征肠道组织中产生IL-10的Tregs。这些结果将为今后与从人肠组织中分离的Treg细胞进行比较研究奠定基础。具体目的是测试三个不同但相关的假设：(1)产生IL-10的CD4 T细胞（CD4+IL -10 +）对共生细菌抗原反应是存在于肠黏膜中的自然存在的Treg群体，是负责肠道免疫稳态的主要群体；(2)肠道CD4+IL-10+ treg需要肠道菌群的发育和维持；(3)肠道Tregs通过旁观者抑制抑制结肠炎效应T细胞的发育和维持。这些研究将促进我们对肠道Tregs的理解，并将为免疫系统如何保持对肠道细菌群所代表的巨大抗原挑战的耐受性提供见解。在大多数小鼠模型中，对细菌菌群的免疫调节缺陷是慢性肠道炎症的共同特征，并被假定发生在炎症性肠病（IBD）患者中，如克罗恩病和溃疡性结肠炎。这些研究将为操纵Treg功能作为恢复IBD中失调的T细胞反应的治疗方法提供基础。

DESCRIPTION (provided by applicant): Regulatory T cells are a CD4+ T cell subset with immunosuppressive activity that have been identified in humans and mice. These cells exert tolerance through a dominant mechanism that has obvious therapeutic implications for intervention in autoinflammatory diseases and transplantation. We have identified IL-10 producing CD4+ T cells in the normal mouse intestine that are reactive to enteric bacterial antigens and have Treg function in vitro and in vivo. We speculate that this population develops from mature, naive CD4 T cell precursors that recognize enteric bacterial antigens, and that IL-10 can be a useful marker with which to identify and study these cells. In this proposal, we will make use of a novel antigen-specific model of colitis based on the DO11.10 TCR transgenic mouse to examine the origin, function and maintenance of intestinal Tregs. We will also employ a new IL-10 reporter knock-in mouse to provide a functional marker that can be used to identify, isolate and characterize IL-10 producing Tregs in the intestinal tissues. These results will form the basis for future comparative studies with Treg cells isolated from human intestinal tissues. The specific aims are to test three distinct, but related hypotheses: (1) IL-10 producing CD4 T cells (CD4+IL - 10+) reactive to commensal bacterial antigens are a naturally occurring Treg population that exist in the intestinal mucosae and are the principal population responsible for intestinal immune homeostasis; (2) intestinal CD4+IL-10+ Tregs require the enteric flora for development and maintenance; and (3) intestinal Tregs suppress the development and maintenance of colitogenic effector T cells through bystander inhibition. These studies will advance our understanding of intestinal Tregs and will provide insights into how the immune system maintains tolerance to the enormous antigenic challenge represented by the enteric bacterial flora. Defective immunoregulation to the bacterial flora is a common feature of chronic intestinal inflammation in most murine models and is postulated to occur in patients with inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. These studies will provide a basis for manipulation of Treg function as a therapeutic approach to restoring dysregulated T cell responses in IBD.